White matter diseases are a frequent diagnosis problem in adult
patients. They are divided into leucodystrophy, defined by abnormal
white matter from the beginning, and leucoencephalopathy, with an
initial normal white matter. In addition, two different natures have to
be considered: vascular and non-vascular. Vascular diseases are mainly
acquired and related to atherosclerosis. Genetic vascular disorders are
mostly secondary to Notch3 mutations, defined as cerebral autosomal
dominant arteriopathy with subcortical infarcts and leucoencephalopathy
(CADASIL). Occurrence of leucoaraiosis and lacunae on T2 sequences, and
microbleeds on Gradient Echo sequences, strongly suggest this diagnosis.

This review describes MR in the adult leucoencephalopathies and in
multiple sclerosis (MS). The first part will focus on MR patterns of
vascular and non-vascular adult leucoencephalopathies, the second part
on MR findings in MS and MS-related diseases. Specific MR patterns in
both diseases will be summarized and compared.

The term 'leucoencephalopathies' encompasses disorders
mainly involving the brain white matter. Hereditary
leucoencephalopathies, often called leucodystrophies, can be separated
into three categories: 1) metabolic leucoencephalopathies caused by
defects in gene coding for enzymes or proteins involved in the cell
metabolism, and for which the diagnosis is currently based on
biochemical analysis of plasma and urines samples; 2) leucodystrophies
caused by defects in gene coding for proteins not directly involved in
metabolic pathways and for which the diagnosis is directly based on gene
testing; and 3) leucoencephalopathies without any known biochemical
abnormalities or mutated genes.

One of the most frequently described genetic vascular
leucoencephalopathies is CADASIL. (1) It is an autosomal dominant
condition, causing recurrent subcortical strokes, subcortical dementia,
migraine with aura, and depression. The mutated gene Notch3 was mapped
to the long arm of chromosome 19. (2) Neuroimaging findings consist of
both focal lacunar infarcts and diffuse white matter ischaemic changes
known as leucoaraiosis, seen as high-intensity signal on T2-weighted MR
imaging. Lacunae are located in the thalamus, basal ganglia, internal
capsule and brainstem (central pons). Leucoaraiosis typically involves
the periventricular area, mainly in the posterior regions, typically
sparing the subcortical U-fibres (Figure 2). In addition, Gradient Echo
sequences often show hypointense lesions, resulting from cerebral
microhaemorrhages. (3,4)

Recently, more specific MR findings have been described, such as
involvement of the anterior part of the temporal pole, the external
capsule, and the corpus callosum. (5) In the presence of these findings,
it is sometimes possible to suspect CADASIL at the outset and to avoid,
thereby, a false diagnosis of MS. These MR lesions represent different
consequences of the underlying angiopathy.

[FIGURE 1 OMITTED]

Leucoencephalopathy Due to Col IV Mutation

The occurrence of leucoencephalopathy, lacunar lesions, micro- and
macrohaemorrhages, porencephaly, cataract, infantile-onset hemiparesis
and retinal arteriolar tortuosity in the presence of a positive family
history has been recently related to mutation of the Col IV A1 gene.
(6,7)

TREX 1 Leucoencephalopathies

Recently, a dominant vascular leucoencephalopathy was related to
mutation of the TREX1 gene. It is characterized by retinal vasculopathy
and brain leucoencephalopathy. (8)

[FIGURE 2 OMITTED]

Non-vascular Leucodystrophies

These conditions can be related to inborn errors of metabolism or
genetic leucodystrophies. Main causes of leucodystrophies with
identified enzyme deficiency are summarized in Tables 1 and 2.

It is difficult to discuss in detail the MR aspect of all inherited
metabolic leucodystrophies. However, common radiological aspects often
seen are:

Interestingly, some leucodystrophies with known mutated genes have
specific patterns of MR. The following section concerns these genetic
leucodystrophies with highly specific MR patterns.

Megalencephalic Leucoencephalopathy with Subcortical Cysts

First described in 1995, megalencephalic leucoencephalopathy with
subcortical cysts (MLC) is characterized by: 1) clinical symptoms:
macrocephaly occurring in the first year of life, mild-to-moderate
cognitive defects and progressive spasticity, leading to a progressive
and slow handicap and epileptic seizures (in half of the cases); 2)
neuroradiological findings (Figure 3): diffuse, symmetrical white matter
lesions, with constant frontoparietal and anterotemporal subcortical
cysts. (9-11) Histological analysis consists of spongiform white matter
changes related to vacuoles between the outer lamellae of myelin
sheaths, sparing the axons. These changes could be related to splitting
of the myelin lamellae along the intraperiod line or incomplete
compaction. (9)

[FIGURE 3 OMITTED]

MLC is observed worldwide. (12,13) A high incidence is seen in
Northern India in the Agarwals population, (14) and in Turkey. (10,11)
The mode of transmission is consistent with autosomal recessive
inheritance. A first gene, mapped to 22qtel, (15) KIAA0027, named MLC1
(MIM no. 604004), was identified by Leegwater et al. (16) A founder
effect was seen in some populations. (17) However, close to 20% of the
patients are not linked to MLC1 gene mutations, (18,19) confirming the
genetic heterogeneity.

Leucoencephalopathy with Brainstem and Spinal Cord Involvement and
High Lactates

A new ataxic leucodystrophy with recessive inheritance was
described by van der Knaap et al. in 2003, (20) characterized by a
slowly progressive paraparesis, and proprioceptive and cerebellar ataxia
with childhood onset. This entity was referred to as leucoencephalopathy
with brainstem and spinal cord involvement and high lactate (LBSL). MR
patterns in LBSL are characterized by extensive demyelination, involving
corpus callosum, pyramidal fibres of corona radiata, posterior part of
the internal capsules, brainstem (cerebellar peduncles, intraparenchymal
and mesencephalic trigeminal nerves). The spinal cord is frequently also
involved, especially with demyelination of lateral corticospinal tracts,
dorsal columns and medial lemniscus. (21)

Demyelination can also involve white matter of the cerebellum. (22)
MR spectroscopy patterns consist of a significant decrease in
N-acetylaspartate, an increase in myoinositol, normal or mildly elevated
choline, and elevated lactate within the white matter. However, a few
patients with normal content of lactates have been described. (23,24)
The mutated gene has been mapped to chromosome 1 and was recently
identified as DARS2. This gene encodes mitochondrial aspartyl-tRNA
synthetase resulting in reduced enzymatic activity of the mutant
protein. (25)

NHD

NHD, also known as polycystic lipomembranous osteodysplasia with
sclerosing leucoencephalopathy (PLOSL/ MIM221770), is an autosomal
recessive disease characterized by association of presenile dementia and
destruction of bones. (26) Since the first descriptions in the 1970s,
more than 150 cases have been reported from Japan, Finland and other
countries. (27) First symptoms typically appear in the third decade,
consisting of pain and swelling of the wrists and ankles, and extremity
bone fractures related to minor trauma. Radiographs showed trabecular
loss in the distal ends of the long bones and cystic alterations in the
fingers and toes, sparing skull and axial skeleton. Cystic cavities
contain fat cells and lipid membranes of 1-2 ?m thickness. (26)
Neurological symptoms occurred 10 years later, including epileptic
seizures, frontal-type dementia and choreiform movements. Frontal
dysfunction was assessed by positron emission tomography studies. Death
usually occurred 20 years later (mean age: 50). Progressive MR
abnormalities can be seen: cerebral atrophy, increased bicaudate ratio
and basal ganglia calcifications, with initially normal cerebral white
matter. The end of the radiological evolution is characterized by a
diffuse cerebral atrophy together with increased signal intensity of the
cerebral white matter on T2-weighted images. The demyelination typically
involves the entire white matter. Brain histopathology is characterized
by frontal loss of myelin and nerve fibres, with axonal spheroids,
lipid-loaded macrophages and extensive astrocytic reaction and gliosis.
(26-29) In addition, reduction in size of basal ganglia, mainly caudate
nuclei, is observed. Vascular alterations are consistently observed:
they consist of concentric thickening of the vascular wall with
narrowing or obliteration of the lumen of small arterioles and
capillaries. Immunostaining for Col IV showed thickened and multiple
basement membranes. Based on these changes, pathogenesis was explained
by lipid metabolism abnormalities or vascular hypoplasia.

The mutated gene (DAP12) was mapped to 19q13.1. It was recently
identified, with a founder mutation in some populations, as in Finland.
(27) Different types of mutations were found, including single base
mutation or large deletions.

Genetic heterogeneity for this disorder has been established
because one Swedish and one Norwegian family have been described who met
diagnostic criteria for PLOSL criteria but do not have a DPA12 mutation.
(30) Other reports described a second mutated gene, TREM2, possibly
involved in this disease. (31)

The pathogenesis of PLOSL remains unclear. Two hypotheses have been
proposed: 1) vascular damage with resultant blood--brain barrier
breakdown and consequent ischaemia, resulting in oligodendroglial and
axonal damage, including spheroid formation, and widespread loss of
axons and myelin sheaths; and 2) abnormalities of systemic lipid
metabolism, resulting in breakdown of the myelin sheaths. (32) Vascular
origin is likely part of the mechanism of this disease.

Adult-onset Autosomal Dominant Leucodystrophy

Adult-onset autosomal dominant leucodystrophy (ADLD; OMIM = 169500)
was first reported in an American-Irish kindred in 1984. (33) Symptoms
onset is typically seen between the age of 50 and 60. Autonomic
dysfunction (bladder and bowel dysfunction, orthostatic hypotension) is
frequently preceded by cerebellar and pyramidal dysfunction.

On MRI, the signal-intensity changes are most prominent in the
frontoparietal and cerebellar white matter (especially the peduncles).
In advanced disease, abnormalities are also seen in the occipital and,
to a lesser extent, temporal lobes. (34) Involvement of the entire
corticospinal tract and corpus callosum is seen in all symptomatic
subjects (Figure 4). Sparing or less severe alteration of the
periventricular white matter is typical. Signal-intensity changes can
often be seen in asymptomatic individuals, ranging from subtle changes
in the upper part of the corticospinal tract to a more extensive
involvement.

Due to clinical (especially the long-term evolution with a frequent
survival rate of 20 years) and MR findings, a diagnosis of MS is often
mistakenly made in these patients.

Neuropathology has been reported in three patients, who showed
extensive loss of myelin, isolated and confluent patches, involving
cerebrum and cerebellum white matter. Preservation of oligodendroglia
and relative absence of astrogliosis in the demyelinated areas without
any inflammation of the brain were regarded as unique features.

[FIGURE 4 OMITTED]

The gene that causes the disease is located on chromosome 5q31.6.
(35) Identification of a tandem genomic duplication resulting in a copy
of the gene encoding the nuclear lamina protein lamin B1 (LMNB1) was
made in 2006. (36)

Alexander Disease

Alexander disease is a progressive, usually fatal, neurological
disorder, mainly occurring in childhood. Onset of the disease is usually
before the age of 2 years (72% of the published cases). (37) Symptoms
include mental retardation, bulbar dysfunction, seizures, macrocephaly
and spasticity, resulting in death usually by the age of 10 years.
Histological findings consist of loss of myelin in the frontal lobes.
Juvenile forms (age of onset: 2-12 years) are characterized by
occurrence of bulbar symptoms and a slower evolution. More recently, a
delayed onset (adulthood) form has been described, characterized by a
slower progressive course, with ataxia and palatal myoclonus in absence
of cognitive defect and macroencephaly. (38-40) Other phenotypes have
been reported: oscillopsia, primary ovarian failure, thyroid hormone
abnormalities, hypothermia, microcoria, dysautonomia and acute evolution
of the disease with death occurring in less than 2 months. (41,42)

The prognosis depends on the age of onset: mean survival is close
to 3.6 years in infantile onset, 8.1 in juvenile onset and 15.0 in
adulthood onset.

In adulthood, MR findings consist of hypointense signals on T2
sequences involving grey matter, brainstem and cervical cord, with
marked atrophy. Interestingly, frontal lobes are spared in these late
onset forms. Histological findings (massive accumulation in the
Rosenthal fibres) are shared between the different forms of the disease.
Accumulation of fibres is mainly seen in subpial and subependymal
regions in the juvenile forms, and in cerebellum and brainstem in the
adulthood forms. Most of the cases are related to mutations in the gene
encoding glial fibrillary acidic protein (GFAP), resulting in Rosenthal
fibre deposition in astrocytes. (45,46) Both GFAP and LMNB1 are members
of the intermediate filament superfamily. (47)

The classic and most common variant of childhood ataxia with
central nervous system (CNS) hypomyelination/leucoencephalopathy with
vanishing white matter (CACH/VWM) has its onset in childhood, at age 2-6
years. It is characterized by chronic progressive neurological
deterioration with cerebellar ataxia, milder spasticity and mental
decline. The evolution is characterized by episodes of major and rapid
deteriorations following different triggers, such as minor head trauma,
febrile infections and acute fright. During these episodes, loss of
motor faculties and hypotonia are observed, with coma and death in some
cases. Recovery is usually incomplete, with neurological sequellae and
occurrence of death in a few years. (48) Phenotypic variation has been
described depending on the age of onset.

Decreased fetal movements, oligohydramnios, growth failure and
microcephaly (48) are seen in antenatal forms. Soon after birth, rapid
deterioration occurs in these patients, including vomiting, axial
hypotonia, apnoeic episodes, respiratory failure, coma and death within
a few months. (50,51)

Infantile CACH, also called 'Cree leucoencephalopathy',
was described among the Cree Indians. (52) Onset is between 3 and 9
months of age and leads to a rapid death. Milder variants of the disease
with an adolescent or adult onset have been recently described:
asymptomatic forms, late onset (beginning at 40), isolated psychiatric
symptoms or dementia. (53,54)

Primary or secondary ovarian failure can be encountered among
females of all different disease severities. Ovarian atrophy can be
found on abdominal echography. (55-57)

The MRI shows an abnormal signal of almost all of the cerebral
white matter, but sparing the U-fibres. Serial MRs show progressive
rarefaction and cystic degeneration of the affected white matter, which
is replaced by water (Figure 5). This change is best seen on proton
density and fluid-attenuated inversion recovery (FLAIR) sequences as
regions of high-signal (demyelination) and hypointense signal (cystic
degeneration). Increased diffusivity is found on diffusion-weighted
sequences, corresponding to the cystic degeneration. Abnormal lesions
never enhance following Gd administration. In addition, MR examination
(notably on T1 sequences) can show a radiating, stripe-like pattern
within the rarefied and cystic white matter, suggesting remaining tissue
strands. (58)

There is no correlation between MR abnormalities and clinical
symptoms, since patients with typical MR can be clinically or mildly
asymptomatic. At the end of the evolution, the entire cerebral
hemispheric white matter may have vanished.

Demyelination can sometimes involve the brainstem and cerebellar
white matter, resulting in atrophy, but without cystic degeneration.

On macroscopic examination the cerebral white matter varies from
gelatinous to cavitary. The frontoparietal white matter, particularly
deep and periventricular, seems to be more commonly involved, with
relative sparing of the temporal lobe, optic system, corpus callosum and
internal capsule.

Increase of oligodendrocyte size is found in the areas of
demyelination. The astrocytes are dysmorphic with blunt broad processes.

Five mutated genes EIF2B1-5 have been identified so far. (59-62)
They encode the five subunits of eukaryotic translation initiation
factor eIF2B (elF2B[alpha], [beta], [gamma], [delta] and [epsilon]).
Two-thirds of the patients with VWM have mutations in EIF2B5 which is
the largest subunit.

Demyelinating Diseases

MS

By now, the MR patterns in MS are well established. They were
initially described in the early 1980s by Lukes and colleagues, (63) and
in 1997 Barkhof developed a system of classification that has been
incorporated into the current international diagnostic criteria for MS.
(63-65) These criteria for dissemination in space are defined as
follows: 1) Either one Gd-enhancing lesion or nine T2-hyperintense
lesions; 2) At least one infratentorial lesion; 3) At least one
juxtacortical lesion; 4) At least three periventricular lesions.

Typical MS lesions are seen as >3 mm in diameter,
periventricular with extensions (Dawson fingers) into the adjacent white
matter, and ovoid morphology.

They involve corpus callosum, internal capsule, cerebellar
peduncles and juxtacortical areas. Using FLAIR, the percentage of
juxtacortical lesions in MS was 30%. Lesions in the cortex make up a
substantial percentage of lesions in histopathological studies, up to
59% in one series. Their presence is related to myelinated axons
extending well into the cortex, and contrasts with hypoxic/ischaemic
diseases where the direct subcortical zone, containing the U-fibres, is
typically spared. (63)

In addition, chronic T1 hypointense lesions ('black
holes'), are often found in MS patients. They consist of focal
areas of relatively severe tissue injury, including axonal injury,
matrix destruction and myelin loss. Acute MS lesions also appear
T1-hypointense as a result of transient oedema, although these are not
true T1-black holes. T1 hypointensity may linger months after an acute
event with such lesions evolving to isointensity (loss of oedema or
repair) or persisting as chronic, permanent hypointensity. A true T1
black hole is a chronic hypointensity. These lesions cannot be
determined with certainty on an MR image obtained on one occasion,
because, by definition, a chronic black hole must persist for at least 6
months.

Other Inflammatory Disorders

Devic's Disease

Neuromyelitis optica (NMO, also known as Devic's disease) is
an idiopathic, severe, demyelinating disease of the CNS that
preferentially affects the optic nerve and spinal cord. MRI findings of
the brain at the onset of NMO are typically normal in contrast to MS.
They may show non-specific white matter lesions and optic nerve
enhancement by Gd injection, during acute optic neuritis. An exception
is brainstem lesions, which can occur in isolation or as a rostral
extension of cervical myelitis (Figure 6).

During evolution of the disease, MR can find asymptomatic white
substance lesions in 60% of the patients. Spinal cord involvement is
quite different from MS myelitis: lesions are longitudinally extensive,
and span three or more contiguous vertebral segments.

The presence of a highly specific serum autoantibody marker
(NMO-IgG) differentiates NMO from MS. These antibodies react with the
water channel aquaporin-4. (66)

Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is considered as a
monophasic demyelinating disease of the CNS. Young children and
adolescents are most commonly affected. Numerous cases among adults and
even elderly patients have been recently reported. (67)

[FIGURE 6 OMITTED]

MR Findings

MR findings are quite different from MS: frequent grey matter
involvement (basal ganglia or cortical lesions), uncommon involvement of
the corpus callosum, simultaneous enhancement of the lesions by Gd
injection and importance of the oedema reaction (Figure 7).